tbuckley/cabot-search huggingface dataset:
Comprehensive de novo mutation discovery with HiFi long-read sequencing
Authors: Erdi Kucuk, Bart P. G. H. van der Sanden, Luke O’Gorman, Michael Kwint, Ronny Derks, Aaron M. Wenger, Christine Lambert, Shreyasee Chakraborty, Primo Baybayan, William J. Rowell, Han G. Brunner, Lisenka E. L. M. Vissers, Alexander Hoischen, Christian Gilissen
Journal: Genome Medicine (2023)

Abstract Background Long-read sequencing (LRS) techniques have been very successful in identifying structural variants (SVs). However, the high error rate of LRS made the detection of small variants (substitutions and short indels &lt; 20 bp) more challenging. The introduction of PacBio HiFi sequencing makes LRS also suited for detecting small variation. Here we evaluate the ability of HiFi reads to detect de novo mutations (DNMs) of all types, which are technically challenging variant types and a major cause of sporadic, severe, early-onset disease. Methods We sequenced the genomes of eight parent–child trios using high coverage PacBio HiFi LRS (~ 30-fold coverage) and Illumina short-read sequencing (SRS) (~ 50-fold coverage). De novo substitutions, small indels, short tandem repeats (STRs) and SVs were called in both datasets and compared to each other to assess the accuracy of HiFi LRS. In addition, we determined the parent-of-origin of the small DNMs using phasing. Results We identified a total of 672 and 859 de novo substitutions/indels, 28 and 126 de novo STRs, and 24 and 1 de novo SVs in LRS and SRS respectively. For the small variants, there was a 92 and 85% concordance between the platforms. For the STRs and SVs, the concordance was 3.6 and 0.8%, and 4 and 100% respectively. We successfully validated 27/54 LRS-unique small variants, of which 11 (41%) were confirmed as true de novo events. For the SRS-unique small variants, we validated 42/133 DNMs and 8 (19%) were confirmed as true de novo event. Validation of 18 LRS-unique de novo STR calls confirmed none of the repeat expansions as true DNM. Confirmation of the 23 LRS-unique SVs was possible for 19 candidate SVs of which 10 (52.6%) were true de novo events. Furthermore, we were able to assign 96% of DNMs to their parental allele with LRS data, as opposed to just 20% with SRS data. Conclusions HiFi LRS can now produce the most comprehensive variant dataset obtainable by a single technology in a single laboratory, allowing accurate calling of substitutions, indels, STRs and SVs. The accuracy even allows sensitive calling of DNMs on all variant levels, and also allows for phasing, which helps to distinguish true positive from false positive DNMs.
Changes in Physician Work Hours and Implications for Workforce Capacity, 2001 to 2021—Reply
Authors: Anna L. Goldman, Michael L. Barnett
Journal: JAMA Internal Medicine (2023)

In Reply We thank Drs Chiu, Chiang, and Hsu for their thoughtful letter. They argue that the rapid growth of hospital medicine as a subspecialty may account for the decreasing gender gap in weekly physician work hours that we identified in our study.1
IL-21 induces pyroptosis of Treg cells via Akt–mTOR–NLRP3–caspase 1 axis in eosinophilic chronic rhinosinusitis
Authors: Lihong Chang, Haotian Wu, Weiqiang Huang, Yue Li, Ye Chen, Xia Li, Zhouzhou Yao, Xiaohong Chen, Xiaoping Lai, Rui Zheng, Zizhen Huang, Xifu Wu, Gehua Zhang
Journal: Journal of Allergy and Clinical Immunology (2023)
Association between the Finnish Diabetes Risk Score and cancer in middle-aged and older adults: Involvement of inflammation
Authors: Yu Peng, Peng Wang, Jianxiao Gong, Fubin Liu, Yating Qiao, Changyu Si, Xixuan Wang, Huijun Zhou, Fangfang Song
Journal: Metabolism (2023)

BackgroundDiabetes is associated with increased risk of common cancers. However, evidence of cancer risk in individuals with different diabetes risk is still scarce, and the underlying mechanism remains unknown. Therefore, we aimed to evaluate the relationship between the Finnish Diabetes Risk Score (FINDRISC) and risks of cancer incidence and mortality in a prospective study, and to explore whether low-grade inflammation partially mediated the association.MethodsA total of 330,384 participants aged 37 to 73 at baseline from the UK Biobank database was included in this study. The Cox proportional hazards model was used to examine the relationship of the FINDRISC and low-grade inflammation with risks of cancer incidence and mortality. Then, we estimated the contribution of higher FINDRISC to risks of overall and site-specific cancers. In addition, the role of low-grade inflammation in the association between FINDRISC and cancer risks was investigated through mediation analysis.ResultsThe increased FINDRISC was dose-dependently associated with higher incidence and mortality risks of overall cancer and an overwhelming majority of site-specific cancers. The higher FINDRISC was a strong contributor to incidence of eighteen site-specific cancers and mortality of fourteen site-specific cancers, with a population-attributable risk of 8.1 %–39.1 %, 14.2 %–39.7 %, respectively. Additionally, low-grade inflammation mainly mediated the association between the FINDRISC and risks of incidence and mortality of overall cancer, colorectal cancer, etc.ConclusionsOur findings highlighted the higher FINDRISC as critical risk factors of cancer incidence and mortality, partially mediated by low-grade inflammation. Individuals with increased risk of diabetes are also needed to be concerned about cancer prevention.
Considerations Regarding Autism Spectrum Disorders and Cardiometabolic Diseases
Authors: Changbo Jin, Wenming Shi
Journal: JAMA Pediatrics (2023)

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Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial
Authors: Melissa L. Abel, Nobuyuki Takahashi, Cody Peer, Christophe E. Redon, Samantha Nichols, Rasa Vilimas, Min-Jung Lee, Sunmin Lee, Meenakshi Shelat, Robbie Kattappuram, Linda Sciuto, Danielle Pinkiert, Chante Graham, Donna Butcher, Baktiar Karim, Ajit Kumar Sharma, Justin Malin, Rajesh Kumar, Christopher W. Schultz, Shubhank Goyal, Jaydira del Rivero, Manan Krishnamurthy, Deep Upadhyay, Brett Schroeder, Tristan Sissung, Manoj Tyagi, Jung Kim, Yves Pommier, Mirit Aladjem, Mark Raffeld, William Douglas Figg, Jane Trepel, Liqiang Xi, Parth Desai, Anish Thomas
Journal: Clinical Cancer Research (2023)

Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations.In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels.Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥ grade 4 adverse events occurred. Tumor regressions were observed in two patients with neuroendocrine prostate cancer and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer.ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors.
Effect Measure Modification by Birth Weight on the Association Between Overweight or Obesity and Hypertension in Children and Adolescents
Authors: James T. Nugent, Yuan Lu, Yanhong Deng, Mona Sharifi, Jason H. Greenberg
Journal: JAMA Pediatrics (2023)

This cross-sectional study examines the prevalence of hypertension among children and adolescents with low, very low, normal, or high birth weight.
Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Children Aged ⩾6 Years with Cystic Fibrosis and at Least One <i>F508del</i> Allele: A Phase 3, Open-Label Clinical Trial
Authors: Claire Wainwright, Susanna A. McColley, Paul McNally, Michael Powers, Felix Ratjen, Jonathan H. Rayment, George Retsch-Bogart, Erica Roesch, Neil Ahluwalia, Anna Chin, Chenghao Chu, Mengdi Lu, Prema Menon, David Waltz, Tanya Weinstock, Laura Zelazoski, Jane C. Davies
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

A 24-week, phase 3, open-label study showed elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was safe and efficacious in children aged 6-11 years with cystic fibrosis (CF) and one or more
Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial): A Multicenter, Randomized, Controlled Clinical Trial
Authors: Ellen A. Gorman, Jennifer Rynne, Hannah J. Gardiner, Anthony J. Rostron, Jonathan Bannard-Smith, Andrew M. Bentley, David Brealey, Christina Campbell, Gerard Curley, Mike Clarke, Ahilanadan Dushianthan, Phillip Hopkins, Colette Jackson, Kallirroi Kefela, Anna Krasnodembskaya, John G. Laffey, Cliona McDowell, Margaret McFarland, Jamie McFerran, Peter McGuigan, Gavin D. Perkins, Jonathan Silversides, Jon Smythe, Jacqui Thompson, William S. Tunnicliffe, Ingeborg D.M. Welters, Laura Amado-Rodríguez, Guillermo Albaiceta, Barry Williams, Manu Shankar-Hari, Daniel F. McAuley, Cecilia M. O’Kane
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Rationale: Mesenchymal stromal cells (MSCs) may modulate inflammation, promoting repair in COVID-19-related Acute Respiratory Distress Syndrome (ARDS). Objectives: We investigated safety and efficacy of ORBCEL-C (CD362-enriched, umbilical cord-derived MSCs) in COVID-related ARDS. Methods: This multicentre, randomised, double-blind, allocation concealed, placebo-controlled trial (NCT03042143) randomised patients with moderate-to-severe COVID-related ARDS to receive ORBCEL-C (400million cells) or placebo (Plasma-Lyte148). Measurements: The primary safety and efficacy outcomes were incidence of serious adverse events and oxygenation index at day 7 respectively. Secondary outcomes included respiratory compliance, driving pressure, PaO2/FiO2 ratio and SOFA score. Clinical outcomes relating to duration of ventilation, length of intensive care unit and hospital stays, and mortality were collected. Long-term follow up included diagnosis of interstitial lung disease at 1 year, and significant medical events and mortality at 2 years. Transcriptomic analysis was performed on whole blood at day 0, 4 and 7. Main Results: 60 participants were recruited (final analysis n=30 ORBCEL-C, n=29 placebo: 1 in placebo group withdrew consent). 6 serious adverse events occurred in the ORBCEL-C and 3 in the placebo group, RR 2.9(0.6-13.2)p=0.25. Day 7 mean[SD] oxygenation index did not differ (ORBCEL-C 98.357.2], placebo 96.667.3). There were no differences in secondary surrogate outcomes, nor mortality at day 28, day 90, 1 or 2 years. There was no difference in prevalence of interstitial lung disease at 1year nor significant medical events up to 2 years. ORBCEL-C modulated the peripheral blood transcriptome. Conclusion: ORBCEL-C MSCs were safe in moderate-to-severe COVID-related ARDS, but did not improve surrogates of pulmonary organ dysfunction. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT03042143. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
First-in-human phase I/Ib study of QL1706 (PSB205), a bifunctional PD1/CTLA4 dual blocker, in patients with advanced solid tumors
Authors: Yuanyuan Zhao, Yuxiang Ma, Aimin Zang, Ying Cheng, Yiping Zhang, Xiangcai Wang, Zhendong Chen, Song Qu, Jianbo He, Chuanben Chen, Chuan Jin, Dongyuan Zhu, Qingshan Li, Xianling Liu, Wuyun Su, Yi Ba, Yanrong Hao, Junmin Chen, Guoping Zhang, Shenhong Qu, Yong Li, Weineng Feng, Mengxiang Yang, Baorui Liu, Weiwei Ouyang, Jin Liang, Zhuang Yu, Xiaoyan Kang, Shilin Xue, Guihong Yang, Wei Yan, Yingying Yang, Zhi Liu, Yufeng Peng, Bill Fanslow, Xian Huang, Li Zhang, Hongyun Zhao
Journal: Journal of Hematology & Oncology (2023)

Abstract Background QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t 1/2 ) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. Methods In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. Results Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. Conclusions QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.
A local subset of mesenchymal cells expressing the transcription factor Osr1 orchestrates lymph node initiation
Authors: Pedro Vallecillo-García, Mickael Orgeur, Glenda Comai, Sophie Poehle-Kronawitter, Cornelius Fischer, Marleen Gloger, Camille E. Dumas, Claudia Giesecke-Thiel, Sascha Sauer, Shahragim Tajbakhsh, Uta E. Höpken, Sigmar Stricker
Journal: Immunity (2023)
Considerations Regarding Autism Spectrum Disorders and Cardiometabolic Diseases—Reply
Authors: Chathurika S. Dhanasekara, Chanaka N. Kahathuduwa
Journal: JAMA Pediatrics (2023)

In Reply On behalf of our coauthors, we appreciate Jin and Shi taking time to review our article1 and sharing their thoughts in a Letter to the Editor. We address the 2 concerns raised by the authors in this response.
Novel tumor therapy strategies targeting endoplasmic reticulum-mitochondria signal pathways
Authors: Hongzheng Wu, Wanxin Chen, Zhenni Chen, Xianping Li, Min Wang
Journal: Ageing Research Reviews (2023)

Organelles form tight connections through membrane contact sites, thereby cooperating to regulate homeostasis and cell function. Among them, the contact between endoplasmic reticulum (ER), the main intracellular calcium storage organelles, and mitochondria has been recognized for decades, and its main roles in the ion and lipid transport, ROS signaling, membrane dynamic changes and cellular metabolism are basically determined. At present, many tumor chemotherapeutic drugs rely on ER-mitochondrial calcium signal to function, but the mechanism of targeting resident molecules at the mitochondria-associated endoplasmic reticulum membranes (MAM) to sensitize traditional chemotherapy and the new tumor therapeutic targets identified based on the signal pathways on the MAM have not been thoroughly discussed. In this review, we highlight the key roles of various signaling pathways at the ER-mitochondria contact site in tumorigenesis and focus on novel anticancer therapy strategies targeting potential targets at this contact site.
A Protocolized Management of Walled-Off Necrosis (WON) Reduces Time to WON Resolution and Improves Outcomes
Authors: Serge Baroud, Vinay Chandrasekhara, Andrew C. Storm, Ryan J. Law, Eric J. Vargas, Michael J. Levy, Tala Mahmoud, Fateh Bazerbachi, Aliana Bofill-Garcia, Rabih Ghazi, Daniel B. Maselli, John A. Martin, Santhi Swaroop Vege, Naoki Takahashi, Bret T. Petersen, Mark D. Topazian, Barham K. Abu Dayyeh
Journal: Clinical Gastroenterology and Hepatology (2023)
Host cell entry and neutralisation sensitivity of the SARS-CoV-2 XBB.1.16 lineage
Authors: Inga Nehlmeier, Amy Kempf, Prerna Arora, Anne Cossmann, Alexandra Dopfer-Jablonka, Metodi V Stankov, Sebastian R Schulz, Hans-Martin Jäck, Georg M N Behrens, Stefan Pöhlmann, Markus Hoffmann
Journal: Cellular and Molecular Immunology (2023)

Despite previous circulation of the highly transmissible and antibody evasive BA.2.75, BQ.1, XBB.1 and XBB.1.5lineages, the share of infections caused by the SARS-CoV-2 lineage XBB.1.16has gradually increased in India in early 2023, resulting in XBB.1.16being the dominating SARS-CoV-2 lineage in India today.Since a similar trend may also take place in other countries and information on the biological properties of the XBB.1.16lineage is scarce, we conducted a rapid assessment of the SARS-CoV-2 XBB.1.16lineage with respect to its ability to enter cells and evade neutralisation by antibodies.The newly emerged SARS-CoV-2 XBB.1.16lineage (also dubbed as Arcturus), which harbours a unique combination of spike (S) protein mutations (Fig. 1a), was first described in India in January 2023 and rapidly became the dominating lineage (https://covspectrum.org/ [1]) (Fig. 1b).Here we performed a rapid assessment of the SARS-CoV-2 XBB.1.16lineage regarding its ability to enter cells and evade neutralisation by antibodies using S proteincarrying pseudovirus particles (pp), which constitute a suitable model to study host cell entry of SARS-CoV-2 and its neutralisation [2].For comparison, particles bearing the S protein of the ancestral B.1 lineage (B.1 pp ) or S proteins of Omicron sublineages BA.5 (BA.5 pp ), CH.1.1 (CH.1.1 pp ), XBB.1 (XBB.1 pp ), or XBB.1.5(XBB.1.5pp ) were used.In line with expectations, BA.5 pp entered Vero (African green monkey, kidney), 293 T (human, kidney) and Huh-7 (human, liver) cells with higher efficiency compared to B.1 pp (1.6-3.9xhigher, respectively), while entry into Caco-2 (human, colon) and Calu-3 (human, lung) cells was less efficient (1.6-1.9xreduced, compared to B.1 pp ) [3] (Fig. 1c).CH.1.1 pp and XBB.1 pp displayed comparable to slightly higher entry efficiency for Vero, 293 T and Huh-7 cells compared to B.1 pp (1.1x-1.9xhigher, compared to B.1 pp ), while Caco-2 and Calu-3 cell entry was even less efficient as compared to BA.5 pp (2.3-3.8xreduced, compared to B.1 pp ) (Fig. 1c).In accordance with literature, cell entry of XBB.1.5pp was generally increased compared to XBB.1 pp (1.2-1.5xhigher, compared to XBB.1 pp ) [4] and the same observation was made for XBB.1.16pp (1.3-1.6xhigher, compared to XBB.1 pp ) (Fig. 1c).
Epidemiologic Burden and Projections for Eosinophilic Esophagitis–Associated Emergency Department Visits in the United States: 2009-2030
Authors: Angela Y. Lam, Jeffrey K. Lee, Stephanie Coward, Gilaad G. Kaplan, Evan S. Dellon, Albert J. Bredenoord, Vipul Jairath, Eileen Crowley, Milli Gupta, Humberto Jijon, Yasmin Nasser, Christopher N. Andrews, Mirna Chehade, Nirmala Gonsalves, Ikuo Hirano, Christopher Ma
Journal: Clinical Gastroenterology and Hepatology (2023)
Transcriptomic and Proteomic of Gastrocnemius Muscle in Peripheral Artery Disease
Authors: Luigi Ferrucci, Julián Candia, Ceereena Ubaida-Mohien, Alexey Lyashkov, Nirad Banskota, Christiaan Leeuwenburgh, Stephanie Wohlgemuth, Jack M. Guralnik, Mary Kaileh, Dongxue Zhang, Robert Sufit, Supriyo De, Myriam Gorospe, Rachel Munk, Charlotte A. Peterson, Mary M. McDermott
Journal: Circulation Research (2023)

Few effective therapies exist to improve lower extremity muscle pathology and mobility loss due to peripheral artery disease (PAD), in part because mechanisms associated with functional impairment remain unclear. To better understand mechanisms of muscle impairment in PAD, we performed in-depth transcriptomic and proteomic analyses on gastrocnemius muscle biopsies from 31 PAD participants (mean age, 69.9 years) and 29 age- and sex-matched non-PAD controls (mean age, 70.0 years) free of diabetes or limb-threatening ischemia. Transcriptomic and proteomic analyses suggested activation of hypoxia-compensatory mechanisms in PAD muscle, including inflammation, fibrosis, apoptosis, angiogenesis, unfolded protein response, and nerve and muscle repair. Stoichiometric proportions of mitochondrial respiratory proteins were aberrant in PAD compared to non-PAD, suggesting that respiratory proteins not in complete functional units are not removed by mitophagy, likely contributing to abnormal mitochondrial activity. Supporting this hypothesis, greater mitochondrial respiratory protein abundance was significantly associated with greater complex II and complex IV respiratory activity in non-PAD but not in PAD. Rate-limiting glycolytic enzymes, such as hexokinase and pyruvate kinase, were less abundant in muscle of people with PAD compared with non-PAD participants, suggesting diminished glucose metabolism. In PAD muscle, hypoxia induces accumulation of mitochondria respiratory proteins, reduced activity of rate-limiting glycolytic enzymes, and an enhanced integrated stress response that modulates protein translation. These mechanisms may serve as targets for disease modification.